Alum is the most widely used adjuvant in current subunit vaccines against infectious agents. Mucosal tissues represent the main portal of entry of pathogens. In contrast with the general bloodstream in the systemic compartment, mucosal tissues contain a large number of IgA producing cells. This immunoglobulin isotype contributes to the protection of exposed mucosal surfaces via a number of mechanisms including prevention of pathogen binding to host cells (epithelial cells and dendritic cells), neutralization of toxins in the lumen, and neutralization of viruses within epithelial cells. Injected vaccines can induce high levels of IgG responses in the bloodstream, but they are not effective at inducing secretory IgA responses which are needed for optimal protection of mucosal surfaces. In contrast with injected vaccines, mucosal vaccines delivered through the oral, rectal, nasal or sublingual routes target Mucosal-Associated Lymphoid Tissues where they can induce innate signals necessary for induction of secretory IgA responses. Despite decades of research on mucosal vaccines, to date, only two oral vaccines and one intranasal vaccine are licensed for use in the US. This proposal will address the overall hypothesis that the adjuvant alum triggers innate signals that restrict the breath of antibody responses and prevent the production of IgA. Our newly generated data suggest that a family of molecules produced by myeloid cells plays a central role in preventing IgA production by alum-based injected vaccines and targeting those molecules will improve protection by increasing IgA production. Aim 1 will focus on the mechanisms underlying innate suppression of IgA responses by myeloid cells in non-mucosal sites. Aim 2 will identify the cells and signaling pathways targeted by pharmacological agents inhibiting this family of molecules to regulate induction of systemic and mucosal immune responses after systemic immunization. Aim 3 will establish whether strategies targeting the innate suppressors of IgA responses promote broad systemic and mucosal immunity and can protect a relevant animal model against infection with an enteric virus.